This project examines mitochondrial functioning in old age and in pathological states in which decreased energy transduction by mitochondria may compromise survival of neurones. We have investigated the frequency of occurrence of a major deletion (4.8 Kb) in mitochondrial (mt) DNA in four defined brain regions (cerebral cortex, cerebellum, hippocampus and striatum), as a function of aging in the rat. mt-DNA codes for subunits of complexes I, III and IV of the mitochondrial respiratory chain as well as complex V (the ATP- synthase), ribosomal and t-RNA's. The magnitude of the major deletion which we have studied is such as to make transcription completely incompetent for the affected DNA molecule; however, complementation with other DNA molecules within the same mitochondrion is likely to occur. We found increases with aging of approximately 6, 10 and 20- fold in the incidence of the 4.8 Kb deletion, as a fraction of total genomes, when cerebral cortex, hippocampus and striatum, respectively, were compared in 6 month and 22-23 month old rats. However, the deleted genomes still represent a very small fraction of the total (less than 1%) in old-age. Whether they are important in the functioning of the tissue likely depends upon (a) whether distribution is even, or if instead there is mosaicism among neurons, and (b) the complement of other forms of mutation which also prevent transcription of mt-DNA. This is a joint project with Dr. C.F. Filburn of LBC, NIA.